Angiogenesis is a phenomenon in which a new vascular network is formed from an existing blood vessel and is observed mainly in a microvessel. Angiogenesis is originally a physiological phenomenon and is essential for blood vessel formation in fetal life, but it is usually observed only at a limited site such as endometrium or follicle or at a limited period such as a wound healing process in adults. However, pathological angiogenesis is observed in a disease such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoid choroidal angiopathy, diabetic macular edema, psoriasis vulgaris or atherosclerosis, and closely relates to the progress of pathological conditions of these diseases. It is considered that angiogenesis is regulated by balance between its promoting factor and inhibitory factor, and angiogenesis is caused by disruption of the balance (see Molecular Medicine vol. 35, special issue, “Molecular Mechanism of Symptoms and Pathological conditions”, Nakayama Syoten, 73-74 (1998) and Protein, Nucleic Acid, Enzyme and extra number, “The Most Advanced Development of New Drugs”, Kyoritsu Shuppan, 1182-1187 (2000)).
A vascular endothelial growth factor (hereinafter abbreviated as “VEGF”) is a factor which specifically acts on a receptor (Flt-1, KDR/Flk-1 or the like) present on the surface of vascular endothelial cells, thereby to promote proliferation and migration of the vascular endothelial cells, construction of a capillary vessel network due to vasculogenesis, and plays a very important role in incidence of angiogenesis. Accordingly, there have been many reports on attempts to treat a disease associated with angiogenesis by inhibiting VEGF to control the incidence of angiogenesis. Examples of drugs to be used for the treatment include indolin-2-one derivatives (see WO 98/50356), phthalazine derivatives (see WO 98/35958), quinazoline derivatives (see WO 97/30035), anthranilic acid amide derivatives (see WO 00/27819), 2-aminonicotinic acid derivatives (see WO 01/55114), 4-pyridylalkylthio derivatives (see WO 04/078723) and the like.
However, there is no description on cyclic compounds having a pyrimidinylalkylthio group in these patent publications.
On the other hand, cyclic compounds having a pyrimidinylalkylthio group is reported in WO 03/016306. This patent publication relates to pyrimidine derivatives having an HIV inhibitory activity, however, this patent publication only discloses enormous combinations of chemical structures and does not make specific disclosure of cyclic compounds having a pyrimidinylalkylthio group according to the present invention at all.